Vaccination is most probably the most cost-effective medical intervention that has saved countless human lives during its history of more than two hundred years. Among its most spectacular successes count the eradication of smallpox as well as the virtual disappearance of diphtheria, tetanus and paralytic poliomyelitis. Andre, F. E. (2003) Vaccinology: past achievements, present roadblocks and future promises. Vaccine 21: 593-5. In addition, vaccination has controlled, in at least part of the world, yellow fever, pertussis, Haemophilus influenzae type b, measles, mumps, rubella, typhoid and rabies. Still, important infections remain unpreventable as well as incapable of being treated by a therapeutic vaccine. Moreover, effectiveness of a number of vaccines is less than would be desirable. Clearly, the creation of new vaccines has not become routine, and development of immunization agents against certain diseases may require new approaches. The following examples illustrate some of the current challenges.
About 50% of ten-year-old American and European children are seropositive for herpes simplex virus HSV-1. Stanberry, L. R. Herpes simplex virus vaccines. In: Vaccines (Plotkin, S. A. et al., eds.) 5th edition. 2008. Saunders Elsevier. Prevalence increases to 70-80% in the sixth and seventh decades. Herpes simplex virus HSV-2 prevalence rises during adolescence and reaches peaks of 20% and 30% in Europe and the United States, respectively. Potentially life-threatening infection can occur in subjects with skin disorders. HSV infection of the eye may affect the conjunctiva, cornea or retina and can cause blindness. Perinatal herpes infection can include encephalitis or disseminated infection. Infection in immune-compromised subjects such as HIV patients may also be life-threatening. HSV infection has many complications, resulting in significant morbidity and mortality. It is noteworthy that acute genital herpes infection significantly increases the risk of HIV acquisition. HSV-1 and HSV-2 infections involve replication at the site of entry and spread of virus along nerve fibers to sensory ganglia where latency is established. The viruses can reactivate periodically/sporadically, migrate back to the periphery and replicate in the periphery. A number of prophylactic and therapeutic vaccine candidates were developed and tested clinically. Stanberry, L. R. (2008). At this time, no effective therapeutic or prophylactic vaccine is available. It has been argued that a successful therapeutic or prophylactic vaccine should elicit powerful antibody as well as T cell (Th-1) responses. Cunningham, A. L. and Mikloska, Z. (2001) The holy grail: immune control of human herpes simplex virus infection and disease. Herpes 8 (Supplement 1): 6A-10A.
It has been suggested that the goal of developing a prophylactic HSV-1 or HSV-2 vaccine may be too ambitious and that the focus should be on generating a therapeutic vaccine. In this regard, it is encouraging that a vaccine was able to be developed that shows effectiveness in preventing shingles (herpes zoster). Johnson, R. et al. (2007) Prevention of herpes zoster and its painful and debilitating consequences. Int. J. Infect. Dis. 11 (Supplement 2): S43-S48. The latter disease is caused by reactivation in sensory ganglia of varicella-zoster virus (VZV), another alphaherpes virus. The vaccine, made from the live attenuated Oka strain, is >60% effective in reducing the burden of illness or postherpetic neuralgia. This protection is associated with a boosted cell-mediated immune response. The Oka strain was also utilized to develop a highly effective, live attenuated vaccine for the prevention of chicken pox/varicella. Gershon, A. A. et al. Varicella vaccine. In: Vaccines (Plotkin, S. A. et al., eds.) 5th edition. 2008. Saunders Elsevier. Therefore, it can be argued that it should not be impossible to create effective herpes simplex vaccines. It is noted that development of an even more effective herpes zoster vaccine (or a varicella vaccine that cannot reactivate) would be a worthwhile goal.
Influenza is characterized typically by sudden fever, sore throat, cough, headache, myalgia, chills, anorexia and fatigue. Bridges, C. B. et al. Inactivated influenza vaccines. In: Vaccines (Plotkin, S. A. et al., eds.) 5th edition. 2008. Saunders Elsevier; Belshe, R. B. et al. Influenza vaccine-live. In: Vaccines (Plotkin, S. A. et al., eds.) 5th edition. 2008. Saunders Elsevier. Influenza is a high morbidity but relatively low mortality disease. Seasonal attack rates typically are between 5% and 20%. The death toll from complications of the illness is considerable. According to the WHO, the worldwide yearly death toll may lie between 250,000 and 500′000. Influenza viruses are enveloped and contain a segmented negative-sense RNA genome. The spherical viral particles have spikes consisting of hemagglutinin (HA) and neuraminidase (NA). HA is the major antigen against which the host antibody response is directed. Influenza A viruses are classified into subgroups based on the properties of their envelope proteins HA and NA. Sixteen H(A) and nine N(A) subtypes are currently known. Presently, influenza viruses of subtypes H1N1, H1N2 and H3N2 are circulating in humans. Influenza type A also infects birds including poultry, pigs, horses, dogs and even sea mammals. All known HA and NA subtypes could be isolated from wild aquatic birds, which constitute a natural reservoir and a source of genes for pandemic A-type viruses. Because of the error-prone mode of replication and selection in the host, influenza A and B viruses undergo gradual antigenic change in their two surface antigens, the HA and NA proteins. This phenomenon known as antigenic drift necessitates continuous vigilance and yearly review/update of strains used for vaccine production. Pandemics result from antigenic shift, i.e., introduction into the human population of a novel influenza A virus containing either only a novel HA subtype or both novel HA and NA subtypes.
Whole-virus inactivated influenza vaccines have been in use since 1945. Typically, vaccine viruses have been propagated in the allantoic cavities of embryonated hens' eggs. More recently, such vaccines also have been made from viruses amplified in mammalian cell lines. Since the 1970s, most inactivated vaccines are subvirus or split vaccines. Typical vaccines in use are trivalent, comprising HAs from H1N1 and H3N2 subtype influenza A strains and an influenza B strain (referred to as TIV). The variable efficacy of the inactivated virus vaccines (TIV), the short duration of protection, adverse reaction to parenteral administration (the primary route used) and the absence of induction of effective cellular immunity has led to the development of live attenuated influenza virus vaccines (LAIV). An intranasal vaccine was made based on temperature-sensitive and cold-adapted influenza virus A and B strains.
An updated systematic review and meta-analysis of vaccine efficacy and effectiveness data was published not long ago. Osterholm, M. T. et al. (2012) Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect. Dis. 12: 36-44. The analysis focused on studies carried out in the United States and published between 1967 and 2011. Studies were selected based on a set of criteria that were intended to ensure scientific rigor and, to the extent possible, exclude bias. All criteria were fulfilled by 17 randomized, controlled trials showing vaccine efficacy (95% CI>0), of which trials 8 related to TIV and 9 to LAIV. The trials covered 24 influenza seasons and included almost 54,000 participants. Of the trials that revealed significant efficacy for TIV, 6 involved 18-64-year-old participants, one children aged 6-23 months and one included all age groups and reported a combined efficacy. The mean vaccine efficacy revealed by these trials was 62%. It is noted that none of the trials specifically tested vaccine effects in adults 65 years of age and older or in children aged 2-17. Of particular interest is a study on young children that was carried on over two seasons in both of which there was a good match between vaccine and circulating strains. Hoberman, A. et al. (2003) Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial. JAMA 290: 1608-16. Vaccine efficacy in the first season was 66% and in the second −7%. Regarding LAIV, mean efficacy from eight studies in children aged 6 months to 7 years was 78%. Osterholm, M. T. et al. (2012). Three studies on subjects aged 18-49 revealed no significant protection. One study in persons over 60 showed an overall efficacy of 42%, but efficacy in 60-69-year-olds seemed to be considerably lower than that in persons over 70. No qualifying study related to children aged 8-17 or adults between 50 and 59 years of age.
Nine of 14 observational studies that satisfied the inclusion criteria reported effectiveness of seasonal influenza vaccine. Osterholm, M. T. et al. (2012). These studies included 17 embedded or cohort analyses. Six of the 17 analyses (35%) showed significant effectiveness against medically attended, laboratory-confirmed influenza. In children of 6-59 months, significant vaccine effectiveness was found in 3 of 8 seasons (38%). One of two such studies reported vaccine effectiveness in subjects aged 65 and older. Based on these data it can be concluded that currently available influenza vaccines provide moderate protection against virologically confirmed disease, which protection is not long-lasting. No protection may be obtained in some seasons. Evidence for protection of the highest risk population, i.e., persons 65 years of age or over, is very thin indeed. More effective vaccines are clearly needed. Present vaccines rely largely on the induction of HA antibodies for protective effects. It has been proposed that future influenza vaccines should be capable of inducing potent (effector) T cell responses, i.e., should induce more complete immune responses. Osterhaus, A. et al. (2011) Towards universal influenza vaccines. Phil. Trans. R. Soc. B 366: 2766-73; Thomas, P. G. et al. (2006) Cell-mediated protection in influenza infection. Emerging Infectious Diseases 12: 48-54.
HIV/AIDS is a leading cause of death in Subsaharan Africa and an important cause of mortality worldwide. HIV are lentiviruses which are retroviruses that cause characteristically slow infections, producing disease after long latency periods in the presence of an activated host immune response. HIV include HIV-1 and HIV-2, with HIV-1 being the more aggressive and more rapidly spreading virus. As a first step of the infection process, viral envelope protein gp120 binds to CD4 receptor and then to CCR-5 or CXCR-4 co-receptors on the surface of target cells. CD4 is present in T helper lymphocytes, monocytes-macrophages, follicular DC, Langerhans cells in the skin and microglia in the central nervous system.
At this time, there is no effective vaccine available against HIV/AIDS. A number of observations suggest that, in order to be effective, a vaccine must trigger a substantial cellular immune response. A number of vaccine candidates were tested in clinical trials. Recent pivotal trials made use of viral vectors to induce T-cell responses. To further increase efficacy, these trials also implemented prime-boost regimens. One such phase III trial used a combination of a priming canarypox virus expressing an HIV gp120 antigen and an HIV gp120 boost. Although a trend towards prevention of HIV-1 was found, the vaccine produced no beneficial effects on post-infection virus load or CD4+ cell counts. Draper, S. J. and Heeney, J. L. (2010) Viruses as vaccine vectors for infectious diseases and cancer. Nat. Rev. Microbiology 8: 62-73; Kim, J. H. et al. (2012) HIV vaccines—lessions learned and the way forward. Curr. Opin. HIV AIDS 5: 428-34. Another recent series of trials using replication-incompetent Ad5 expressing various HIV proteins as vaccines did not reveal any indication of efficacy. The latter experiences as well as the realization that a narrow CTL response can lead to the appearance of CTL escape mutants suggest that future vaccine candidates should be capable of inducing complete immune responses including broad CTL responses. Goulder, P. J. R. and Watkins, D. I. (2004) HIV and SIV CTL escape: implications for vaccine design. Nat. Rev. Immunol. 4: 630-40; Barouch, D. H. et al. (2002) Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic lymphocytes. Nature 415: 335-9.
Tuberculosis is caused by Mycobacterium tuberculosis. Smith, K. C. et al. (2008) Tuberculosis vaccines. In: Vaccines (Plotkin, S. A. et al., eds.) 5th edition. 2008. Saunders Elsevier. The disease represents a huge public health problem with approximately one third of the word population infected with the organism, despite widespread vaccination programs. Latent tuberculosis infection is the preclinical state of the disease. Outbreak of disease can occur within weeks or decades from the time of establishment of latent infection. Yearly deaths from tuberculosis range in the millions. The exact immunological mechanisms that underlie human resistance to M. tuberculosis remain to be elucidated. However, it is known that progressive disease is associated with a Th2 or a mixed Th1/Th2 response, whereas a pure Th1 response correlates with protection. Surcel, H-M. et al. (1994) Th1/Th2 profiles in tuberculosis, based on the proliferation and cytokine response of blood lymphocytes to mycobacterial antigens. Immunology 81: 171-6; Schauf, V. et al. (1993) Cytokine gene activation and modified responsiveness to interleukin-2 in the blood of tuberculosis patients. J. Infect. Dis. 168: 1056-9. The Bacille Calmette-Guérin (BCG) vaccines are the oldest vaccines currently in use. Unfortunately, the question whether the vaccines work has not been answered definitively. Efficacies between 0 and 80% have been reported. The exact immune response elicited by BCG vaccination as well as the mechanism of action within the host are not well understood. Smith, K. C. et al. (2008). Animal studies have been infrequent. Smith, D. W. (1985) Protective effect of BCG in experimental tuberculosis. Adv. Tuberc. Res. 22: 1-97. Nevertheless, the available information indicates that protective effects can be transferred with CD4 T-cells, but not with serum. Furthermore, the T-cell response is faster in vaccinated animals, resulting in more rapid macrophage activation.
New and more effective vaccines are clearly needed. The present invention relates to vaccine compositions comprising a replication-competent controlled virus as well as to methods of immunization utilizing the latter compositions.
Replication-competent viruses and virus pairs controlled by a SafeSwitch or a SafeSwitch-like gene switch were disclosed generally in U.S. Pat. Nos. 7,906,312 and 8,137,947.